We use the GENESIS atmospheric general circulation model (GCM) with water isotopic transport and fractionation capabilities to quantify the influence of atmospheric CO2, sea level, and elevation of the Western Cordillera on the δ18O of middle Cretaceous precipitation. The model predicts a systematic increase of nearly 3‰ in the δ18O of North American precipitation due to warming associated with an increase in CO2 from 2 to 12 times pre-industrial levels. In contrast, the specification of lowstand conditions and a high ancestral Western Cordillera reduces the δ18O of North American precipitation locally by as much as 6‰ and 8‰. We compare the simulated δ18O of precipitation with the δ18O of paleosol siderite spherules and find good agreement only when the model includes lowstand conditions and a high ancestral Western Cordillera. Our results imply either that Cretaceous high-latitude paleosol δ18O was influenced by orographic precipitation and the Western Interior Seaway, or that the GCM's hydrological cycle is deficient at high pCO2. Additional paleosol data are needed to resolve this issue.